Combination Chemotherapy With or Without Hypofractionated Radiation Therapy Before Surgery in Treating Patients With Pancreatic Cancer

PRIMARY OBJECTIVES:

I. To evaluate and estimate 18 months overall survival (OS) rate of patients with borderline
resectable pancreatic ductal adenocarcinoma (PDAC) receiving neoadjuvant therapy.

SECONDARY OBJECTIVES:

I. To evaluate and estimate the R0 resection rates in patients receiving each of the two
multimodality treatment regimens.

II. To evaluate and estimate the event-free survival in patients receiving each of the two
multimodality treatment regimens.

III. To evaluate and estimate the pathologic compete response (pCR) rates in patients
receiving each of the two multimodality treatment regimens.

IV. To assess the adverse events (AE) profile and safety of each treatment arm.

TERTIARY OBJECTIVES:

I. To test the effect of the rs2853564 vitamin D receptor (VDR) variant on OS rate and
discover novel candidate genes associated with OS and severe toxicity of chemotherapy by
using genome-wide genotyping approaches.

II. To evaluate risk classification previously developed by Koay et al using normalized area
under the enhancement curve (NAUC).

III. To access prognostic value of NAUC ratio defined as post-neoadjuvant NAUC divided by
pre-neoadjuvant therapy NAUC.

IV. To evaluate risk classification previously developed by Koay et al using delta measure.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan IV over 90
minutes, and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil
IV continuously over 46-48 hours on days 1-2. Treatment repeats every 14 days for 8 courses
in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive oxaliplatin intravenously (IV) over 2 hours, irinotecan IV over 90
minutes, and leucovorin calcium IV over 2 hours on day 1. Patients also receive fluorouracil
IV continuously over 46-48 hours on days 1-2. Treatment repeats every 14 days for 7 courses
in the absence of disease progression or unacceptable toxicity. Patients receive either
stereotactic body radiation therapy (SBRT) or hypofractionated image guided radiation therapy
(HIGRT) on days 1-5 of course 8.

SURGERY Within 4 to 8 weeks after the last dose of chemotherapy (arm A) or of radiation (arm
B), patients considered surgical candidates for resection (after central review) will undergo
surgery at the registering institution.

ADJUVANT CHEMOTHERAPY Within 4-12 weeks from the date of surgery, patients will receive
oxaliplatin IV over 2 hours and leucovorin IV over 2 hours on day 1. Patients also receive
fluorouracil IV continuously over 46-48 hours on days 1-2. Treatment repeats every 14 days
for 4 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 16 weeks for 2 years,
then every 6 months for 5 years.

Inclusion Criteria:

- Confirmation of radiographic stage as borderline resectable disease by real-time
Alliance central radiographic review

- No prior chemotherapy or radiation for pancreatic cancer

- No definitive resection of pancreatic cancer

- Chronic concomitant treatment with strong inhibitors of cytochrome p450, family 3,
subfamily a, polypeptide 4 gene (CYP3A4) is not allowed on this study; patients on
strong CYP3A4 inhibitors must discontinue the drug for 14 days prior to registration
on the study

- Chronic concomitant treatment with strong CYP3A4 inducers is not allowed; patients
must discontinue the drug 14 days prior to the start of study treatment

- No grade >= 2 neuropathy

- No known Gilbert's syndrome or known homozygosity for UGAT1A1*28 polymorphism

- No uncontrolled gastric ulcer disease (grade 3 gastric ulcer disease) within 28 days
of registration

- Not pregnant and not nursing; for women of childbearing potential only, a negative
pregnancy test done =< 7 days prior to registration is required

- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Platelet count >= 100,000/mm^3

- Creatinine =< 1.5 x upper limit of normal (ULN) or

- Calculated (calc.) creatinine clearance > 45 mL/min

- Total bilirubin =< 2.0 mg/dL

- Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) =< 2.5 X upper limit
of normal (ULN)